The inflammation effect is independent of cholesterol, providing
a newly discovered mechanism to cause heart attacks and a new
target for drugs. The inflammation also is linked to abdominal
aortic aneurysms and intracerebral artery aneurysms.

About 40 percent of people with European ancestry have at least
one copy of the variants; 10 percent have two, one from each
parent, said Dr. Eric Topol of Scripps Health, a co-senior author
of the paper,
published in the journal Nature
. (Abstract only, subscription
required for full article). There are 33 variants.

Moreover, the variants are not genetic; they occurs in a "gene
desert" region of DNA called 9p21 found on Chromosome 9. Only a
small percentage of human DNA actually consists of genes; the
functions of the remainder, if they have functions, are mostly
unknown. The study by the Scripps and UCSD researchers gives
evidence of one hitherto undiscovered function.

The variants are SNPs, or single-nucleotide polymorphisms,
one-letter changes in the genetic alphabet.

These specific variants are called "enhancers" in the Nature
paper, because they enhance a certain genetic effect; in this case,
the inflammatory response in the arteries.

"Interestingly, we determined that the 9p21 interval is the
second densest gene desert for predicted enhancers (7.5 per 100 kb)
in the human genome and the one containing the most
disease-associated variants," the paper stated. "These data
indicate that the 9p21 gene desert has an important regulatory
function."

The enhancers trigger interactions with genes located at
considerable distances from each other on the chromosome, Topol
said. That's at odds with conventional genomic science, which
emphasizes proximity as a trigger for interaction.

"This lesson of long-range interactions of a locus of the genome
-- not a gene -- with something that is a gene that's hundreds of
thousands of bases away, is a vital lesson," Topol said.

[caption id="attachment_12085" align="aligncenter" width="420"
caption="A map of genomic interactions linking inflammation,
coronary artery disease, and aneurysms, as published in the Nature
paper. Click on the image for a larger one.

The histogram represents the normalized average number of reads
mapping to each BamH1 donor site. The inner circle links connect
BamH1 acceptor sites for the nine most strongly interacting donor
sites.

b, PCR validation of the long-range interaction between ECAD9
and CDKN2A/B (top) or MTAP (bottom). Arrow indicates the specific
product."]

Topol is a cardiologist who has plunged into the world of
genomics, the study of all the genes in an organism, in this
instance, humans. However, Topol said in an interview a
surprisingly large amount of "genetic" activity has been found to
occur outside of genes. This underscores that DNA is not the same
as genes; while all genes are made of DNA, only 1.5 percent of
human DNA contains genes.

"This (study) is a template for many other genomic loci not in
genes," Topol said. "Of all the 160 diseases that have been
cracked, about 80 percent of them are not in genes."

Co-authors of the study include Dimple Notani, Xiaoyuan Song
and Bogdan Tanasa of the UCSD Department of Medicine, Howard Hughes
Medical Institute; Xiang-Dong Fu of the UCSD Department of Cellular
and Molecular Medicine; Nathaniel Heintzman and Bing Ren of the
Ludwig Institute for Cancer Research; and Nazli G. Rahim and Eric
J. Topol of Scripps Genomic Medicine, Scripps Translational Science
Institute and The Scripps Research Institute.